Closing the gap of ubiquitin activation

It is well appreciated that proteins are involved in all processes of life ranging from cell proliferation to cell survival and death. With such a wide spectrum of activities, which in many cases have opposing results, proteins must be tightly regulated to ensure the right outcome at the right time. Indeed, proteins are regulated at various levels prior to, during, and after their translation. The latter type of regulation, known as posttranslational modification (PTM), occurs via modifiers that covalently bind the target protein. These modifiers comprise small molecules, as in the case of phosphorylation, acetylation, and methylation, and also small polypeptides, such as ubiquitin (Ub) and ubiquitin-like proteins (UBLs). Ub is a highly conserved 76-residue protein, which is covalently linked to target proteins mainly via an isopeptide bond between its C-terminal glycine (Gly) and a lysine (Lys) side chain on a target protein, a process known as ubiquitination (1). Ubiquitination refers to a family of modifications, since proteins can be modified with monoubiquitin (Ub) on 1 or several lysines or with Ub chains (2, 3). With such a wide range of modifications, it is not surprising that ubiquitination plays a role in many different processes including protein degradation, activation, and localization. Accordingly, improper regulation of ubiquitination has been observed in many human diseases including cancer, Alzheimer’s disease, and Parkinson’s disease (4). Therefore, understanding the molecular mechanisms of ubiquitination is of high interest not only for basic research but also for the development of novel therapeutic applications. Before its conjugation to a target protein, Ub or UBL undergoes an activation process mediated by an activating enzyme (E1) (5). While each UBL has its own E1, activation of Ub occurs mainly via the E1, Uba1. Activation of both Ub and UBL comprises 3 steps: 1) adenylation of the Ub/UBL C-terminal Gly … [↵][1]1To whom correspondence may be addressed. Email: reuvenw{at}ekmd.huji.ac.il. [1]: #xref-corresp-1-1